{"gene":"CR1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1988,"finding":"CR1 contains distinct C3b and C4b recognition sites: the NH2-terminal two SCRs of LHR-A determine C4b specificity, while the NH2-terminal two SCRs of LHR-B and LHR-C each contain a C3b binding site. Recombinant full-length CR1 expressed in COS cells mediates rosette formation with C4b- and C3b-coated erythrocytes and has factor I-cofactor activity for C3(ma) cleavage.","method":"Deletion mutagenesis of cDNA constructs expressed in COS cells; rosette formation assay; factor I-cofactor activity assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic deletion mutagenesis with functional readouts (rosetting and cofactor activity), multiple constructs tested, foundational paper widely replicated","pmids":["2972794"],"is_preprint":false},{"year":1997,"finding":"CR1 (CD35) functions as a cellular receptor for C1q. Biotinylated/radioiodinated C1q binds specifically to CR1-transfected K562 cells and to immobilized recombinant soluble CR1 (rsCR1). The C1q collagen domain mediates binding, and C3b dimers partially inhibit binding. Surface plasmon resonance in physiological saline yielded an apparent equilibrium dissociation constant of 3.9 nM.","method":"Radioligand binding to transfected K562 cells; SPR kinetics with immobilized rsCR1; inhibition assays with collagen domain fragments and C3b dimers","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (radiolabeled binding, SPR kinetics, competitive inhibition) in single rigorous study","pmids":["9324355"],"is_preprint":false},{"year":2000,"finding":"CR1/CD35 functions as a cellular receptor for mannan-binding lectin (MBL). Radioiodinated MBL binds immobilized soluble CR1 with an apparent equilibrium dissociation constant of ~5 nM. The MBL carbohydrate-binding site is not involved (N-acetyl-d-glucosamine does not inhibit binding). C1q competes with MBL for the same or adjacent CR1 binding site. CR1 mediates erythrocyte adhesion to immobilized MBL and functions as a phagocytic receptor on PMNs for MBL-IgG-opsonized bacteria.","method":"Radioligand binding to immobilized sCR1; competition assays; erythrocyte adhesion assay; phagocytosis assay on PMNs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (radioligand binding, competition, functional phagocytosis), rigorous controls","pmids":["11120776"],"is_preprint":false},{"year":2002,"finding":"The principal C3b/C4b binding site of CR1 (modules 15–17, residues 901–1095) adopts an extended head-to-tail arrangement with flexibility at the module 16–17 junction. Structure-guided mutagenesis identified a positively charged surface patch on module 15 critical for C4b binding, and basic side chains on module 16 (on the same face) required for both C3b and C4b binding.","method":"NMR structure determination of CCP modules 15–17; structure-guided mutagenesis with functional binding assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure combined with mutagenesis and functional validation in single study","pmids":["11955431"],"is_preprint":false},{"year":1994,"finding":"CR1 has two distinct ligand-binding sites: Site 1 (SCR-1 and SCR-2) binds C4b and is cofactor for C4b cleavage; Site 2 (SCR-8 and SCR-9) binds both iC3/C3b and C4b and is cofactor for cleavage of both. Cofactor activity maps entirely to sequences required for binding. Modifications to either site can increase activity for both ligands.","method":"Substitution mutagenesis of CR1 constructs expressed in COS cells; ligand binding assays; factor I-cofactor cleavage assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with direct functional readouts, replicated and consistent with structural data","pmids":["8175757"],"is_preprint":false},{"year":1986,"finding":"CR1 undergoes tissue-specific phosphorylation: PMA and FMLP induce phosphorylation of CR1 in phagocytic cells (neutrophils, monocytes, eosinophils) but not in non-phagocytic cells (B lymphocytes, erythrocytes). CR1 phosphorylation is associated with activation of phagocytic function. CR3 and FcR are not phosphorylated under the same conditions.","method":"32PO4 metabolic labeling; immunoprecipitation and SDS-PAGE autoradiography; PMA/FMLP stimulation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct metabolic phosphorylation labeling with immunoprecipitation, multiple cell types tested, clear specificity controls","pmids":["3484510"],"is_preprint":false},{"year":1993,"finding":"CR1 cross-linking in human neutrophils activates phospholipase D (PLD) and triggers transient intracellular Ca2+ mobilization. CR1 mediates adhesion of complement-opsonized particles but also participates in engulfment signaling. PMA potentiates CR1-induced PLD activation while impairing phospholipase C activation.","method":"Anti-CR1 antibody cross-linking; diacylglycerol and PLD activity assays; intracellular Ca2+ fluorometry; phagocytosis assays with anti-receptor antibodies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling readouts in single lab, antibody cross-linking approach","pmids":["8326130"],"is_preprint":false},{"year":2013,"finding":"CR1 (CD35) functions as an independent EBV receptor on B cells distinct from CD21. CD35-transduced CD21-negative pre-B and myeloid leukemia cells bind EBV gp350/220 and become latently infected when the fusion receptor HLA II is co-expressed. The temporal, biophysical, and structural characteristics of CD35-mediated EBV infection are distinct from CD21-mediated infection.","method":"Retroviral transduction of CD21-negative cell lines with CD35, CD21, or both; gp350/220 binding assay; viral infection/latency assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional reconstitution in defined cell lines lacking CD21, multiple orthogonal readouts of infection","pmids":["23416052"],"is_preprint":false},{"year":1990,"finding":"Stimulation of CR1 on human monocytes with multivalent polymerized C3b or C3b-Sepharose induces production and release of IL-1β. Monomeric C3b induces intracellular IL-1 but not release. Anti-CR1 antibody also triggers IL-1 production. IL-1 production correlates with CR1 expression levels, establishing CR1-dependent signaling as a pathway to IL-1 induction.","method":"C3b-Sepharose stimulation of adherent monocytes; ELISA and bioassay for IL-1α and IL-1β; inhibition with anti-CR1 antibody; serum-free conditions with LPS controls","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct CR1 ligand and antibody stimulation, multiple controls for LPS contamination, single lab","pmids":["2136879"],"is_preprint":false},{"year":1995,"finding":"CR1 triggering on HIV-infected monocytic cells induces nuclear translocation of NF-κB (p50/p65) and enhances HIV replication 2–4-fold. CR1 stimulation with F(ab')2 anti-CR1 antibodies or C3 fragments on uninfected monocytes also induces NF-κB translocation comparable to TNF-α stimulation.","method":"F(ab')2 anti-CR1 antibody and C3 fragment stimulation; NF-κB nuclear translocation assay; p24 antigen ELISA for viral replication","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct receptor stimulation with mechanistic downstream readout (NF-κB), functional viral replication endpoint, single lab","pmids":["7594489"],"is_preprint":false},{"year":2002,"finding":"CR1 (CD35) on B lymphocytes mediates inhibitory signals: clustering of CR1 with multimeric C3b-like ligands inhibits anti-IgM-induced B cell proliferation, reduces intracellular Ca2+ transients, and reduces phosphorylation of cytoplasmic proteins. This inhibitory effect persists in the presence of IL-2 and IL-15.","method":"Aggregated C3/C3(H2O) stimulation of tonsil B cells; 3H-thymidine proliferation assay; intracellular Ca2+ fluorometry; phosphoprotein analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural CR1-selective ligand used, multiple functional readouts, single lab","pmids":["11884446"],"is_preprint":false},{"year":2006,"finding":"CR1 triggering on human T lymphocytes and T cell lines with anti-CR1 antibodies inhibits proliferation and blocks cytokine protein synthesis (IFN-γ, IL-2) and expression of cyclins A and D3 and PCNA, without affecting immediate-early gene transcription (c-jun, c-fos) or early cytokine mRNA levels. The inhibitory mechanism acts downstream of initial signaling events.","method":"Anti-CR1 antibody stimulation of peripheral T cells and T cell lines; 3H-thymidine proliferation assay; RT-PCR for early gene transcripts; protein expression by Western blot/ELISA","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts (proliferation, mRNA, protein), mechanistic dissection of signaling level, single lab","pmids":["16360013"],"is_preprint":false},{"year":1994,"finding":"An acidic cluster near the N-terminus of the C3b α'-chain (residues 730–739, particularly Glu-736 and Glu-737) is required for C3b interaction with factor B and with CR1 (CR1-dependent factor I cofactor activity). A distinct region (Glu-744, Glu-747) overlaps with factor H but not CR1 binding. MCP binding sites on C3b/C3(H2O) are entirely distinct from those of H and CR1.","method":"Site-directed mutagenesis of C3 residues; factor I cofactor cleavage assay as surrogate binding assay for CR1, factor H, and MCP interactions","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional assay, single lab","pmids":["7963581"],"is_preprint":false},{"year":1999,"finding":"Acidic residues in C3b α'-chain segment 738–767 (Glu-744, Glu-747, Glu-754/Asp-755, Lys-757/Glu-758) are required for CR1-dependent factor I cofactor activity. CR1 contacts extend over a wider portion of the 727–767 segment than factor H contacts, and CR1 requires basic residues to form the interface with this acidic region of C3b.","method":"Charged-residue mutagenic scan of C3 residues 738–767; factor I cofactor cleavage assay for soluble CR1, factor H, and MCP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis, functional readout, single lab","pmids":["9988761"],"is_preprint":false},{"year":2005,"finding":"CR1 has two distinct functional sites (Site 1: CCPs 1–3; Site 2: CCPs 8–10 and 15–17). For the classical pathway C5 convertase, Site 1 mediates dissociation while Site 2 binds the C3b subunit; intervening CCPs are required for proper spatial orientation. Two copies of Site 1 in tandem show up to 58-fold synergistic increase in decay-accelerating activity (DAA) for the C3 convertase, suggesting a dimeric structure for the classical pathway C3 convertase on cell surfaces. Phe82 and the CCP1/CCP2 junction are critical for DAA.","method":"Mutagenesis and expression of CR1 site constructs; decay-accelerating activity assays for C3 and C5 convertases; generation of tandem site constructs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with direct functional assays, single lab","pmids":["16177096"],"is_preprint":false},{"year":1994,"finding":"Soluble CR1 (sCR1) in plasma is generated by proteolytic cleavage of cell-surface CR1. PMN-derived sCR1 lacks the intracellular domain (detected by C-terminal peptide ELISA). PMN release sCR1 at highest levels among leukocytes; fMLP, TNF-α, and LPS accelerate release; GM-CSF sustains CR1 gene expression and total sCR1 release.","method":"Intracellular-domain-specific ELISA; in vitro stimulation of PMN and cell lines; sCR1 size comparison by SDS-PAGE; RT-PCR for CR1 mRNA","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific ELISA distinguishing soluble from membrane form, multiple stimuli tested, single lab","pmids":["7957565"],"is_preprint":false},{"year":1994,"finding":"CR1 on human glomerular podocytes is released as membrane-bound vesicles into urine. Urinary CR1 (uCR1) is membrane-associated (pelleted at 200,000g), enriched in cholesterol and phospholipids, and visualized as membrane vesicles by electron microscopy. Renal transplant allele discordance confirms kidney (podocyte) origin. uCR1 retains C3b-binding function.","method":"Ultracentrifugation; sucrose density gradient; cholesterol/phospholipid measurement; immunoaffinity purification and electron microscopy; SDS-PAGE; renal transplant allele analysis; C3b-binding functional assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods establishing membrane-vesicle nature, podocyte origin confirmed by transplant allotype discordance, functional retention demonstrated","pmids":["8113681"],"is_preprint":false},{"year":1999,"finding":"Hypoxia induces functional CR1 expression on human vascular endothelial cells (HUVECs). CR1 protein increases ~3.7-fold after 48h at 1% O2; CR1 is predominantly intracellular by confocal microscopy. Hypoxic HUVECs bind immune complexes and act as cofactor for factor I-mediated C3b cleavage. LPS and TNF-α also increase HUVEC CR1 expression.","method":"ELISA; confocal colocalization with von Willebrand factor; Western blot; RT-PCR and in situ hybridization; immune complex binding assay; factor I cofactor activity assay","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods, functional validation (cofactor activity), single lab","pmids":["9950773"],"is_preprint":false},{"year":1992,"finding":"CR1 functions as cofactor for factor I-mediated cleavage of both fluid-phase and liposome-bound C4b. CR1 generates primarily C4bi from fluid-phase C4b but C4c/C4d from liposome-bound C4b. CR1 has dual optimal pH (6.0 and 7.5 for fluid phase; 6.0 for solid phase) and is a more potent cofactor for C4b cleavage than for C3b cleavage. MCP acts more efficiently on C3b than C4b.","method":"In vitro cofactor cleavage assay with purified components; SDS-PAGE analysis of cleavage products; pH titration; detergent concentration variation","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, systematic parameter variation, single lab","pmids":["1386357"],"is_preprint":false},{"year":1991,"finding":"Phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages (MDM) is mediated by CR1, CR3, and CR4 together; combined blockade of all three receptors reduces adherence by 80%. IFN-γ activation reduces M. leprae phagocytosis by markedly decreasing surface expression of CR1 (by up to 75%), providing a molecular mechanism for IFN-γ-mediated inhibition of complement-dependent phagocytosis.","method":"Monoclonal antibody blocking of individual and combined complement receptors; light and electron microscopy for adherence/ingestion quantification; flow cytometry for CR1 surface expression after IFN-γ treatment","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blockade with receptor-specific antibodies, EM quantification, IFN-γ mechanistic link, single lab","pmids":["1679838"],"is_preprint":false},{"year":1993,"finding":"CR1 and CR3 mediate productive infection of human monocytes and monocytic cell lines with complement-opsonized HIV-1 and HIV-2 independently of CD4. Blocking CR1 or CR3 with F(ab')2 antibodies abolishes the complement-enhancement of infection. Infection occurs in CD4-negative cell lines (Mono Mac 6, U251-MG) and is not blocked by anti-CD4 antibody.","method":"F(ab')2 antibody blockade of CR1 and CR3; viral infection with complement-opsonized HIV; p24 antigen ELISA; syncytia formation; MTT cytotoxicity; CD4-negative cell line controls","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific F(ab')2 blockade, CD4-negative cell controls, multiple viral readouts, single lab","pmids":["7682158"],"is_preprint":false},{"year":1996,"finding":"The recombinant soluble form of CR1 (rsCD35) is a more effective inhibitor of classical pathway complement activation in vitro than rsCD46 or rsCD55 alone. rsCD35 and rsCD46 regulate alternative pathway cell lysis to a similar extent, whereas rsCD55 is ineffective against the alternative pathway.","method":"In vitro complement activation assays (classical and alternative pathways); cell lysis assays with purified recombinant proteins","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution comparing three inhibitors, single lab","pmids":["8605924"],"is_preprint":false},{"year":1994,"finding":"Two amino acid substitutions (Tyr for Ser37 and Asp for Gly79) at homologous positions in CCP1 and CCP2 of the CR1 C4b-binding site confer C3b binding while retaining C4b binding. Single substitutions are insufficient; the double substitution mimics the C3b-binding site of human CR1.","method":"Site-directed mutagenesis of truncated CR1 constructs; rosette formation with C3b- and C4b-coated erythrocytes; factor I cofactor activity assay","journal":"Journal of immunology (via PMID:8757632, published 1996)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with direct functional validation, single lab","pmids":["8757632"],"is_preprint":false},{"year":1994,"finding":"Murine CR1 (the 6 SCRs appended to mouse CR2) binds both C3b and C4b through a single site requiring SCR-1 as an absolute requirement; deletion of SCRs 5–6 reduces but does not abolish binding of both ligands; constructs lacking SCR-1 (e.g., SCRs 2–6, 2–5, 3–6) lack activity entirely.","method":"Murine CR1/human CR2 chimeric constructs expressed in K562 cells; rosette formation assay with C3b- and C4b-coated erythrocytes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain deletion with functional readout, single lab","pmids":["8144890"],"is_preprint":false},{"year":2018,"finding":"Both C1q and MBL bind CR1 at the same pair of CCP24–25 modules within LHR-D. A CR1 fragment lacking CCP24–25 loses both C1q and MBL binding. C1q binding involves the collagen stalks as a main site plus subsidiary sites on globular heads, contrasting with MBL which uses only the collagen stalks.","method":"CR1 deletion variants (CCP24-25 isolated fragment; CCP22-30 lacking CCP24-25) produced in eukaryotic cells; C1q and MBL binding assays; competitive binding experiments","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined deletion variants with direct binding assays, single lab, corroborates earlier MBL mapping","pmids":["29563915"],"is_preprint":false},{"year":2015,"finding":"CR1 on epithelial cells (podocyte model using CHO cells) reduces C3b deposition by ~80% during classical pathway activation and >95% during alternative pathway activation, primarily via decay-accelerating activity. Deposited C4b/C3b are progressively cleaved with t½ ~30 min by CR1 cofactor activity. CR1 functions intrinsically (only on the cell it is expressed on) and stably binds but does not internalize C4b/C3b-opsonized immune complexes.","method":"CHO cell expression system; C3b deposition assay (classical and alternative pathways); cofactor cleavage kinetics; internalization assay","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cell model, multiple functional assays, quantitative kinetics, single lab","pmids":["26260209"],"is_preprint":false},{"year":2015,"finding":"Co-ligation of CR1 (CD35) and CD46 on activated CD4+ T cells synergistically enhances CD25 expression, granzyme B production, IL-10 secretion, and reduces IFN-γ release, promoting development of a regulatory T cell phenotype. CR1/CD46 double-positive T cells are found in inter-follicular regions of tonsils in vivo.","method":"Anti-CR1 and anti-CD46 antibody co-ligation; ELISA for cytokines; flow cytometry for CD25 and granzyme B; immunohistochemical staining of tonsil sections","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody co-ligation with multiple functional readouts plus in vivo tissue localization, single lab","pmids":["25742728"],"is_preprint":false},{"year":1986,"finding":"Human glomerular podocytes express CR1 as the sole C3 receptor type. Glomerular CR1 binds C3b-coated erythrocytes (not C3dg, C3d, or C3bi), shares functional and antigenic properties with peripheral blood CR1, and has decay-accelerating activity for the C3 convertase. Anti-CR1 F(ab')2 specifically inhibits binding, and immunoprecipitation of surface-labeled glomerular proteins yields CR1 of Mr 205,000.","method":"Rosette adherence assay with defined C3-fragment-coated erythrocytes; indirect immunofluorescence with anti-CR1, anti-CR2, anti-CR3 antibodies; complement convertase decay assay; 125I surface labeling and immunoprecipitation/SDS-PAGE","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (functional adherence, immunofluorescence, convertase decay, immunoprecipitation), replicated across three kidney donors","pmids":["2418113"],"is_preprint":false}],"current_model":"CR1 (CD35) is a multi-modular complement regulatory glycoprotein with two principal ligand-binding sites (Site 1: CCPs 1–3; Site 2: CCPs 8–10 and 15–17) that bind C3b and C4b at distinct but partially overlapping surfaces, and an LHR-D site (CCPs 24–25) that binds the defense collagens C1q and MBL; it inhibits complement activation by decay-accelerating activity toward C3 and C5 convertases and by serving as a cofactor for factor I-mediated cleavage of C3b and C4b, is expressed on erythrocytes, phagocytes, B and T lymphocytes, follicular dendritic cells, and glomerular podocytes where it mediates immune complex transport/clearance, phagocytosis, and transmembrane signaling (NF-κB activation, Ca2+ mobilization, PLD activation, inhibitory signals in B and T cells), and undergoes tissue-specific phosphorylation by protein kinase C in phagocytic cells."},"narrative":{"mechanistic_narrative":"CR1 (CD35) is a modular complement regulatory glycoprotein that restrains complement activation through two complementary enzymatic activities — decay-acceleration of the C3 and C5 convertases and cofactor activity for factor I-mediated cleavage of C3b and C4b [PMID:2972794, PMID:8175757, PMID:26260209]. Its ligand-binding architecture is organized into discrete sites: an N-terminal Site 1 (CCPs 1–3) that mediates C4b binding and convertase decay, and a Site 2 (CCPs 8–10 and 15–17) that binds both C3b and C4b and supports their factor I-dependent cleavage [PMID:8175757, PMID:16177096]. Specificity within these modules is governed by defined residues — the principal C3b/C4b-binding module pair adopts an extended head-to-tail arrangement in which a basic surface patch on module 15/16 contacts the acidic α'-chain segment of C3b, and two substitutions in CCP1/CCP2 are sufficient to convert a C4b-binding site into a C3b-binding one [PMID:11955431, PMID:9988761, PMID:8757632]. CR1 also serves as a receptor for the defense collagens C1q and MBL, both binding a single CCP24–25 module pair in LHR-D, thereby mediating erythrocyte adhesion and phagocytosis of opsonized particles [PMID:9324355, PMID:11120776, PMID:29563915]. Beyond complement regulation, CR1 is an active signaling receptor: ligand engagement or antibody cross-linking on phagocytes triggers phospholipase D activation, Ca2+ mobilization, NF-κB translocation, and IL-1 production, whereas clustering on B and T lymphocytes delivers inhibitory signals that suppress proliferation and cytokine synthesis [PMID:8326130, PMID:2136879, PMID:7594489, PMID:11884446, PMID:16360013]. CR1 is expressed on erythrocytes, phagocytes, lymphocytes, glomerular podocytes, and hypoxic endothelium, and is released both as proteolytically cleaved soluble CR1 from neutrophils and as membrane vesicles shed by podocytes into urine [PMID:3484510, PMID:7957565, PMID:8113681, PMID:9950773, PMID:2418113]. It additionally functions as a CD4-independent entry receptor for complement-opsonized HIV and as an EBV receptor distinct from CD21 [PMID:23416052, PMID:7682158].","teleology":[{"year":1986,"claim":"Established that CR1 is the sole C3b receptor on glomerular podocytes with intrinsic convertase decay activity, extending its role beyond circulating cells to a tissue-resident regulator.","evidence":"Rosette adherence, immunofluorescence, convertase decay assay and surface immunoprecipitation on human glomeruli from three donors","pmids":["2418113"],"confidence":"High","gaps":["Did not define which CCP modules mediate podocyte C3b binding","Physiological consequence of podocyte CR1 loss not addressed"]},{"year":1986,"claim":"Showed CR1 undergoes cell-type-restricted phosphorylation, linking the receptor to active signaling specifically in phagocytes.","evidence":"32PO4 metabolic labeling and immunoprecipitation after PMA/FMLP stimulation across phagocytic and non-phagocytic cells","pmids":["3484510"],"confidence":"High","gaps":["Kinase identity not directly demonstrated","Phosphorylated cytoplasmic residues not mapped"]},{"year":1988,"claim":"Resolved the molecular basis of ligand specificity by mapping distinct C4b and C3b recognition sites to the N-terminal SCRs of separate LHRs, defining CR1 as a multivalent regulator.","evidence":"Deletion mutagenesis of full-length CR1 in COS cells with rosetting and factor I cofactor assays","pmids":["2972794"],"confidence":"High","gaps":["Atomic-level contacts not defined","Quantitative affinities for each site not measured"]},{"year":1992,"claim":"Characterized CR1 as a more potent factor I cofactor for C4b than C3b, distinguishing it functionally from MCP.","evidence":"In vitro reconstituted cofactor cleavage of fluid-phase and liposome-bound C4b with pH and detergent titration","pmids":["1386357"],"confidence":"Medium","gaps":["Single-lab in vitro reconstitution","Cellular relevance of dual pH optima unresolved"]},{"year":1994,"claim":"Refined the two-site model, defining Site 1 (CCP1-2) as C4b-specific cofactor and Site 2 (CCP8-9) as a dual C3b/C4b site, and showed modifications could augment both activities.","evidence":"Substitution mutagenesis in COS cells with ligand binding and cofactor cleavage readouts","pmids":["8175757"],"confidence":"High","gaps":["Did not establish convertase decay contributions of each site","Mechanism of activity enhancement unexplained"]},{"year":1994,"claim":"Pinpointed the acidic C3b α'-chain residues required for CR1 engagement, mapping the complement-side of the interface and distinguishing CR1 from factor H and MCP contact regions.","evidence":"Site-directed mutagenesis of C3 with factor I cofactor cleavage as surrogate binding readout","pmids":["7963581"],"confidence":"Medium","gaps":["Direct binding affinities not measured","Used cofactor activity as proxy for binding"]},{"year":1994,"claim":"Determined that two point substitutions in CCP1/CCP2 are sufficient to graft C3b binding onto a C4b site, defining the residue determinants of ligand discrimination.","evidence":"Site-directed mutagenesis of truncated CR1 with rosetting and cofactor assays","pmids":["8757632"],"confidence":"Medium","gaps":["Structural basis of the gained interaction not shown","Single-lab functional readouts"]},{"year":1994,"claim":"Showed murine CR1 collapses C3b and C4b recognition into a single SCR-1-dependent site, contrasting the multi-site human architecture.","evidence":"Murine CR1/human CR2 chimeric deletion constructs in K562 cells with rosetting","pmids":["8144890"],"confidence":"Medium","gaps":["No quantitative affinity comparison to human CR1","Cofactor activity of murine site not tested"]},{"year":1994,"claim":"Identified soluble plasma CR1 as a proteolytic ectodomain product shed predominantly by neutrophils under inflammatory stimuli, defining a regulated release mechanism.","evidence":"Intracellular-domain-specific ELISA, SDS-PAGE size comparison and RT-PCR after PMN stimulation","pmids":["7957565"],"confidence":"Medium","gaps":["Protease responsible not identified","Cleavage site not mapped"]},{"year":1994,"claim":"Showed podocyte CR1 is shed into urine as functional membrane vesicles, establishing a distinct vesicular release route from the proteolytic neutrophil pathway.","evidence":"Ultracentrifugation, lipid analysis, EM, renal transplant allotype discordance and C3b-binding assay","pmids":["8113681"],"confidence":"High","gaps":["Mechanism of vesicle formation not defined","Functional fate of urinary CR1 unknown"]},{"year":1997,"claim":"Identified CR1 as a high-affinity C1q receptor binding via the collagen domain, expanding its repertoire beyond C3/C4 fragments.","evidence":"Radioligand binding to CR1-transfected K562 cells and SPR on immobilized rsCR1 with competition assays","pmids":["9324355"],"confidence":"High","gaps":["CR1 module mediating C1q binding not localized in this study","Cellular consequence of C1q engagement not addressed"]},{"year":1999,"claim":"Extended the C3b acidic interface to residues 738–767 and showed CR1 contacts a wider segment than factor H, refining the convertase-regulator binding map.","evidence":"Charged-residue mutagenic scan of C3 with cofactor cleavage assays for CR1, factor H and MCP","pmids":["9988761"],"confidence":"Medium","gaps":["No co-structure of the CR1–C3b interface","Proxy assay rather than direct binding"]},{"year":1999,"claim":"Demonstrated hypoxia induces functional CR1 on endothelial cells, identifying a regulated context-dependent expression site relevant to vascular complement control.","evidence":"ELISA, confocal colocalization, Western blot, in situ hybridization and cofactor activity in HUVECs","pmids":["9950773"],"confidence":"Medium","gaps":["Predominantly intracellular localization fate unclear","In vivo relevance not established"]},{"year":2000,"claim":"Identified CR1 as an MBL receptor sharing a binding site with C1q, linking it to lectin-pathway recognition and phagocytosis of opsonized bacteria.","evidence":"Radioligand binding to immobilized sCR1, competition with C1q, erythrocyte adhesion and PMN phagocytosis assays","pmids":["11120776"],"confidence":"High","gaps":["Precise binding module not localized in this study","Signaling downstream of MBL engagement not defined"]},{"year":2002,"claim":"Provided the structure of the principal C3b/C4b-binding module trio, revealing an extended flexible arrangement and the basic surface patches required for ligand contact.","evidence":"NMR structure of CCP15-17 with structure-guided mutagenesis and binding assays","pmids":["11955431"],"confidence":"High","gaps":["No structure of CR1 bound to C3b/C4b","Full-length receptor architecture not resolved"]},{"year":2002,"claim":"Defined CR1 as a negative regulator of B cell activation, showing ligand clustering inhibits BCR-driven proliferation and calcium signaling.","evidence":"Aggregated C3/C3(H2O) stimulation of tonsil B cells with proliferation, Ca2+ and phosphoprotein readouts","pmids":["11884446"],"confidence":"Medium","gaps":["Cytoplasmic signaling effectors not identified","Single-lab antibody/ligand approach"]},{"year":2005,"claim":"Dissected the spatial logic of convertase decay, showing Site 1 mediates dissociation while Site 2 binds C3b, and that tandem Site 1 copies act synergistically, implying a dimeric convertase target.","evidence":"Site mutant and tandem constructs with decay-accelerating activity assays for C3 and C5 convertases","pmids":["16177096"],"confidence":"Medium","gaps":["Proposed convertase dimer not structurally confirmed","Single-lab functional assays"]},{"year":2006,"claim":"Established CR1 as an inhibitory T cell receptor acting downstream of immediate-early transcription to block cytokine protein synthesis and cell-cycle entry.","evidence":"Anti-CR1 stimulation of T cells with proliferation, RT-PCR and protein expression readouts","pmids":["16360013"],"confidence":"Medium","gaps":["Translational/post-transcriptional mechanism not defined","Physiological ligand in T cell context unclear"]},{"year":2013,"claim":"Identified CR1 as an EBV entry receptor distinct from CD21, broadening its role in viral tropism.","evidence":"Retroviral transduction of CD21-negative cell lines with gp350/220 binding and latent infection readouts","pmids":["23416052"],"confidence":"High","gaps":["CR1 module mediating gp350 binding not mapped","In vivo contribution to EBV infection unknown"]},{"year":2015,"claim":"Quantified the intrinsic, non-internalizing protective action of epithelial CR1, showing strong reduction of C3b deposition by decay-acceleration plus progressive cofactor cleavage.","evidence":"CHO podocyte model with classical/alternative pathway deposition, cleavage kinetics and internalization assays","pmids":["26260209"],"confidence":"Medium","gaps":["Model cell system rather than primary podocytes","Single-lab 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Hospital","url":"https://pubmed.ncbi.nlm.nih.gov/2522267","citation_count":21,"is_preprint":false},{"pmid":"29563915","id":"PMC_29563915","title":"C1q and Mannose-Binding Lectin Interact with CR1 in the Same Region on CCP24-25 Modules.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29563915","citation_count":20,"is_preprint":false},{"pmid":"15606620","id":"PMC_15606620","title":"Acquired but reversible loss of erythrocyte complement receptor 1 (CR1, CD35) and its longitudinal alteration in patients with severe acute respiratory syndrome.","date":"2005","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15606620","citation_count":20,"is_preprint":false},{"pmid":"2955969","id":"PMC_2955969","title":"C3b receptor (CR1) expression on the polymorphonuclear leukocytes from patients with systemic lupus erythematosus.","date":"1987","source":"Clinical and experimental 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SLE.","date":"1987","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2958187","citation_count":18,"is_preprint":false},{"pmid":"10396040","id":"PMC_10396040","title":"Role of complement receptors CD21/CD35 in B lymphocyte activation and survival.","date":"1999","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10396040","citation_count":18,"is_preprint":false},{"pmid":"20023417","id":"PMC_20023417","title":"KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer.","date":"2010","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20023417","citation_count":17,"is_preprint":false},{"pmid":"17973862","id":"PMC_17973862","title":"Resistance to Fas-mediated apoptosis in malignant tumours is rescued by KN-93 and cisplatin via downregulation of c-FLIP expression and phosphorylation.","date":"2007","source":"Clinical and 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Analysis based on ligand binding by chimpanzee erythrocyte complement receptor.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8757632","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48901,"output_tokens":7549,"usd":0.129969,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16800,"output_tokens":5799,"usd":0.114488,"stage2_stop_reason":"end_turn"},"total_usd":0.244457,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"CR1 contains distinct C3b and C4b recognition sites: the NH2-terminal two SCRs of LHR-A determine C4b specificity, while the NH2-terminal two SCRs of LHR-B and LHR-C each contain a C3b binding site. Recombinant full-length CR1 expressed in COS cells mediates rosette formation with C4b- and C3b-coated erythrocytes and has factor I-cofactor activity for C3(ma) cleavage.\",\n      \"method\": \"Deletion mutagenesis of cDNA constructs expressed in COS cells; rosette formation assay; factor I-cofactor activity assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic deletion mutagenesis with functional readouts (rosetting and cofactor activity), multiple constructs tested, foundational paper widely replicated\",\n      \"pmids\": [\"2972794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CR1 (CD35) functions as a cellular receptor for C1q. Biotinylated/radioiodinated C1q binds specifically to CR1-transfected K562 cells and to immobilized recombinant soluble CR1 (rsCR1). The C1q collagen domain mediates binding, and C3b dimers partially inhibit binding. Surface plasmon resonance in physiological saline yielded an apparent equilibrium dissociation constant of 3.9 nM.\",\n      \"method\": \"Radioligand binding to transfected K562 cells; SPR kinetics with immobilized rsCR1; inhibition assays with collagen domain fragments and C3b dimers\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (radiolabeled binding, SPR kinetics, competitive inhibition) in single rigorous study\",\n      \"pmids\": [\"9324355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CR1/CD35 functions as a cellular receptor for mannan-binding lectin (MBL). Radioiodinated MBL binds immobilized soluble CR1 with an apparent equilibrium dissociation constant of ~5 nM. The MBL carbohydrate-binding site is not involved (N-acetyl-d-glucosamine does not inhibit binding). C1q competes with MBL for the same or adjacent CR1 binding site. CR1 mediates erythrocyte adhesion to immobilized MBL and functions as a phagocytic receptor on PMNs for MBL-IgG-opsonized bacteria.\",\n      \"method\": \"Radioligand binding to immobilized sCR1; competition assays; erythrocyte adhesion assay; phagocytosis assay on PMNs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (radioligand binding, competition, functional phagocytosis), rigorous controls\",\n      \"pmids\": [\"11120776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The principal C3b/C4b binding site of CR1 (modules 15–17, residues 901–1095) adopts an extended head-to-tail arrangement with flexibility at the module 16–17 junction. Structure-guided mutagenesis identified a positively charged surface patch on module 15 critical for C4b binding, and basic side chains on module 16 (on the same face) required for both C3b and C4b binding.\",\n      \"method\": \"NMR structure determination of CCP modules 15–17; structure-guided mutagenesis with functional binding assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure combined with mutagenesis and functional validation in single study\",\n      \"pmids\": [\"11955431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CR1 has two distinct ligand-binding sites: Site 1 (SCR-1 and SCR-2) binds C4b and is cofactor for C4b cleavage; Site 2 (SCR-8 and SCR-9) binds both iC3/C3b and C4b and is cofactor for cleavage of both. Cofactor activity maps entirely to sequences required for binding. Modifications to either site can increase activity for both ligands.\",\n      \"method\": \"Substitution mutagenesis of CR1 constructs expressed in COS cells; ligand binding assays; factor I-cofactor cleavage assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with direct functional readouts, replicated and consistent with structural data\",\n      \"pmids\": [\"8175757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"CR1 undergoes tissue-specific phosphorylation: PMA and FMLP induce phosphorylation of CR1 in phagocytic cells (neutrophils, monocytes, eosinophils) but not in non-phagocytic cells (B lymphocytes, erythrocytes). CR1 phosphorylation is associated with activation of phagocytic function. CR3 and FcR are not phosphorylated under the same conditions.\",\n      \"method\": \"32PO4 metabolic labeling; immunoprecipitation and SDS-PAGE autoradiography; PMA/FMLP stimulation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct metabolic phosphorylation labeling with immunoprecipitation, multiple cell types tested, clear specificity controls\",\n      \"pmids\": [\"3484510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CR1 cross-linking in human neutrophils activates phospholipase D (PLD) and triggers transient intracellular Ca2+ mobilization. CR1 mediates adhesion of complement-opsonized particles but also participates in engulfment signaling. PMA potentiates CR1-induced PLD activation while impairing phospholipase C activation.\",\n      \"method\": \"Anti-CR1 antibody cross-linking; diacylglycerol and PLD activity assays; intracellular Ca2+ fluorometry; phagocytosis assays with anti-receptor antibodies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling readouts in single lab, antibody cross-linking approach\",\n      \"pmids\": [\"8326130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CR1 (CD35) functions as an independent EBV receptor on B cells distinct from CD21. CD35-transduced CD21-negative pre-B and myeloid leukemia cells bind EBV gp350/220 and become latently infected when the fusion receptor HLA II is co-expressed. The temporal, biophysical, and structural characteristics of CD35-mediated EBV infection are distinct from CD21-mediated infection.\",\n      \"method\": \"Retroviral transduction of CD21-negative cell lines with CD35, CD21, or both; gp350/220 binding assay; viral infection/latency assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional reconstitution in defined cell lines lacking CD21, multiple orthogonal readouts of infection\",\n      \"pmids\": [\"23416052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Stimulation of CR1 on human monocytes with multivalent polymerized C3b or C3b-Sepharose induces production and release of IL-1β. Monomeric C3b induces intracellular IL-1 but not release. Anti-CR1 antibody also triggers IL-1 production. IL-1 production correlates with CR1 expression levels, establishing CR1-dependent signaling as a pathway to IL-1 induction.\",\n      \"method\": \"C3b-Sepharose stimulation of adherent monocytes; ELISA and bioassay for IL-1α and IL-1β; inhibition with anti-CR1 antibody; serum-free conditions with LPS controls\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct CR1 ligand and antibody stimulation, multiple controls for LPS contamination, single lab\",\n      \"pmids\": [\"2136879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CR1 triggering on HIV-infected monocytic cells induces nuclear translocation of NF-κB (p50/p65) and enhances HIV replication 2–4-fold. CR1 stimulation with F(ab')2 anti-CR1 antibodies or C3 fragments on uninfected monocytes also induces NF-κB translocation comparable to TNF-α stimulation.\",\n      \"method\": \"F(ab')2 anti-CR1 antibody and C3 fragment stimulation; NF-κB nuclear translocation assay; p24 antigen ELISA for viral replication\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct receptor stimulation with mechanistic downstream readout (NF-κB), functional viral replication endpoint, single lab\",\n      \"pmids\": [\"7594489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CR1 (CD35) on B lymphocytes mediates inhibitory signals: clustering of CR1 with multimeric C3b-like ligands inhibits anti-IgM-induced B cell proliferation, reduces intracellular Ca2+ transients, and reduces phosphorylation of cytoplasmic proteins. This inhibitory effect persists in the presence of IL-2 and IL-15.\",\n      \"method\": \"Aggregated C3/C3(H2O) stimulation of tonsil B cells; 3H-thymidine proliferation assay; intracellular Ca2+ fluorometry; phosphoprotein analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural CR1-selective ligand used, multiple functional readouts, single lab\",\n      \"pmids\": [\"11884446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CR1 triggering on human T lymphocytes and T cell lines with anti-CR1 antibodies inhibits proliferation and blocks cytokine protein synthesis (IFN-γ, IL-2) and expression of cyclins A and D3 and PCNA, without affecting immediate-early gene transcription (c-jun, c-fos) or early cytokine mRNA levels. The inhibitory mechanism acts downstream of initial signaling events.\",\n      \"method\": \"Anti-CR1 antibody stimulation of peripheral T cells and T cell lines; 3H-thymidine proliferation assay; RT-PCR for early gene transcripts; protein expression by Western blot/ELISA\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts (proliferation, mRNA, protein), mechanistic dissection of signaling level, single lab\",\n      \"pmids\": [\"16360013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"An acidic cluster near the N-terminus of the C3b α'-chain (residues 730–739, particularly Glu-736 and Glu-737) is required for C3b interaction with factor B and with CR1 (CR1-dependent factor I cofactor activity). A distinct region (Glu-744, Glu-747) overlaps with factor H but not CR1 binding. MCP binding sites on C3b/C3(H2O) are entirely distinct from those of H and CR1.\",\n      \"method\": \"Site-directed mutagenesis of C3 residues; factor I cofactor cleavage assay as surrogate binding assay for CR1, factor H, and MCP interactions\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional assay, single lab\",\n      \"pmids\": [\"7963581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Acidic residues in C3b α'-chain segment 738–767 (Glu-744, Glu-747, Glu-754/Asp-755, Lys-757/Glu-758) are required for CR1-dependent factor I cofactor activity. CR1 contacts extend over a wider portion of the 727–767 segment than factor H contacts, and CR1 requires basic residues to form the interface with this acidic region of C3b.\",\n      \"method\": \"Charged-residue mutagenic scan of C3 residues 738–767; factor I cofactor cleavage assay for soluble CR1, factor H, and MCP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis, functional readout, single lab\",\n      \"pmids\": [\"9988761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CR1 has two distinct functional sites (Site 1: CCPs 1–3; Site 2: CCPs 8–10 and 15–17). For the classical pathway C5 convertase, Site 1 mediates dissociation while Site 2 binds the C3b subunit; intervening CCPs are required for proper spatial orientation. Two copies of Site 1 in tandem show up to 58-fold synergistic increase in decay-accelerating activity (DAA) for the C3 convertase, suggesting a dimeric structure for the classical pathway C3 convertase on cell surfaces. Phe82 and the CCP1/CCP2 junction are critical for DAA.\",\n      \"method\": \"Mutagenesis and expression of CR1 site constructs; decay-accelerating activity assays for C3 and C5 convertases; generation of tandem site constructs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with direct functional assays, single lab\",\n      \"pmids\": [\"16177096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Soluble CR1 (sCR1) in plasma is generated by proteolytic cleavage of cell-surface CR1. PMN-derived sCR1 lacks the intracellular domain (detected by C-terminal peptide ELISA). PMN release sCR1 at highest levels among leukocytes; fMLP, TNF-α, and LPS accelerate release; GM-CSF sustains CR1 gene expression and total sCR1 release.\",\n      \"method\": \"Intracellular-domain-specific ELISA; in vitro stimulation of PMN and cell lines; sCR1 size comparison by SDS-PAGE; RT-PCR for CR1 mRNA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific ELISA distinguishing soluble from membrane form, multiple stimuli tested, single lab\",\n      \"pmids\": [\"7957565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CR1 on human glomerular podocytes is released as membrane-bound vesicles into urine. Urinary CR1 (uCR1) is membrane-associated (pelleted at 200,000g), enriched in cholesterol and phospholipids, and visualized as membrane vesicles by electron microscopy. Renal transplant allele discordance confirms kidney (podocyte) origin. uCR1 retains C3b-binding function.\",\n      \"method\": \"Ultracentrifugation; sucrose density gradient; cholesterol/phospholipid measurement; immunoaffinity purification and electron microscopy; SDS-PAGE; renal transplant allele analysis; C3b-binding functional assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods establishing membrane-vesicle nature, podocyte origin confirmed by transplant allotype discordance, functional retention demonstrated\",\n      \"pmids\": [\"8113681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hypoxia induces functional CR1 expression on human vascular endothelial cells (HUVECs). CR1 protein increases ~3.7-fold after 48h at 1% O2; CR1 is predominantly intracellular by confocal microscopy. Hypoxic HUVECs bind immune complexes and act as cofactor for factor I-mediated C3b cleavage. LPS and TNF-α also increase HUVEC CR1 expression.\",\n      \"method\": \"ELISA; confocal colocalization with von Willebrand factor; Western blot; RT-PCR and in situ hybridization; immune complex binding assay; factor I cofactor activity assay\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods, functional validation (cofactor activity), single lab\",\n      \"pmids\": [\"9950773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CR1 functions as cofactor for factor I-mediated cleavage of both fluid-phase and liposome-bound C4b. CR1 generates primarily C4bi from fluid-phase C4b but C4c/C4d from liposome-bound C4b. CR1 has dual optimal pH (6.0 and 7.5 for fluid phase; 6.0 for solid phase) and is a more potent cofactor for C4b cleavage than for C3b cleavage. MCP acts more efficiently on C3b than C4b.\",\n      \"method\": \"In vitro cofactor cleavage assay with purified components; SDS-PAGE analysis of cleavage products; pH titration; detergent concentration variation\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, systematic parameter variation, single lab\",\n      \"pmids\": [\"1386357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages (MDM) is mediated by CR1, CR3, and CR4 together; combined blockade of all three receptors reduces adherence by 80%. IFN-γ activation reduces M. leprae phagocytosis by markedly decreasing surface expression of CR1 (by up to 75%), providing a molecular mechanism for IFN-γ-mediated inhibition of complement-dependent phagocytosis.\",\n      \"method\": \"Monoclonal antibody blocking of individual and combined complement receptors; light and electron microscopy for adherence/ingestion quantification; flow cytometry for CR1 surface expression after IFN-γ treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blockade with receptor-specific antibodies, EM quantification, IFN-γ mechanistic link, single lab\",\n      \"pmids\": [\"1679838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CR1 and CR3 mediate productive infection of human monocytes and monocytic cell lines with complement-opsonized HIV-1 and HIV-2 independently of CD4. Blocking CR1 or CR3 with F(ab')2 antibodies abolishes the complement-enhancement of infection. Infection occurs in CD4-negative cell lines (Mono Mac 6, U251-MG) and is not blocked by anti-CD4 antibody.\",\n      \"method\": \"F(ab')2 antibody blockade of CR1 and CR3; viral infection with complement-opsonized HIV; p24 antigen ELISA; syncytia formation; MTT cytotoxicity; CD4-negative cell line controls\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific F(ab')2 blockade, CD4-negative cell controls, multiple viral readouts, single lab\",\n      \"pmids\": [\"7682158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The recombinant soluble form of CR1 (rsCD35) is a more effective inhibitor of classical pathway complement activation in vitro than rsCD46 or rsCD55 alone. rsCD35 and rsCD46 regulate alternative pathway cell lysis to a similar extent, whereas rsCD55 is ineffective against the alternative pathway.\",\n      \"method\": \"In vitro complement activation assays (classical and alternative pathways); cell lysis assays with purified recombinant proteins\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution comparing three inhibitors, single lab\",\n      \"pmids\": [\"8605924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Two amino acid substitutions (Tyr for Ser37 and Asp for Gly79) at homologous positions in CCP1 and CCP2 of the CR1 C4b-binding site confer C3b binding while retaining C4b binding. Single substitutions are insufficient; the double substitution mimics the C3b-binding site of human CR1.\",\n      \"method\": \"Site-directed mutagenesis of truncated CR1 constructs; rosette formation with C3b- and C4b-coated erythrocytes; factor I cofactor activity assay\",\n      \"journal\": \"Journal of immunology (via PMID:8757632, published 1996)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with direct functional validation, single lab\",\n      \"pmids\": [\"8757632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Murine CR1 (the 6 SCRs appended to mouse CR2) binds both C3b and C4b through a single site requiring SCR-1 as an absolute requirement; deletion of SCRs 5–6 reduces but does not abolish binding of both ligands; constructs lacking SCR-1 (e.g., SCRs 2–6, 2–5, 3–6) lack activity entirely.\",\n      \"method\": \"Murine CR1/human CR2 chimeric constructs expressed in K562 cells; rosette formation assay with C3b- and C4b-coated erythrocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain deletion with functional readout, single lab\",\n      \"pmids\": [\"8144890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Both C1q and MBL bind CR1 at the same pair of CCP24–25 modules within LHR-D. A CR1 fragment lacking CCP24–25 loses both C1q and MBL binding. C1q binding involves the collagen stalks as a main site plus subsidiary sites on globular heads, contrasting with MBL which uses only the collagen stalks.\",\n      \"method\": \"CR1 deletion variants (CCP24-25 isolated fragment; CCP22-30 lacking CCP24-25) produced in eukaryotic cells; C1q and MBL binding assays; competitive binding experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined deletion variants with direct binding assays, single lab, corroborates earlier MBL mapping\",\n      \"pmids\": [\"29563915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CR1 on epithelial cells (podocyte model using CHO cells) reduces C3b deposition by ~80% during classical pathway activation and >95% during alternative pathway activation, primarily via decay-accelerating activity. Deposited C4b/C3b are progressively cleaved with t½ ~30 min by CR1 cofactor activity. CR1 functions intrinsically (only on the cell it is expressed on) and stably binds but does not internalize C4b/C3b-opsonized immune complexes.\",\n      \"method\": \"CHO cell expression system; C3b deposition assay (classical and alternative pathways); cofactor cleavage kinetics; internalization assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cell model, multiple functional assays, quantitative kinetics, single lab\",\n      \"pmids\": [\"26260209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Co-ligation of CR1 (CD35) and CD46 on activated CD4+ T cells synergistically enhances CD25 expression, granzyme B production, IL-10 secretion, and reduces IFN-γ release, promoting development of a regulatory T cell phenotype. CR1/CD46 double-positive T cells are found in inter-follicular regions of tonsils in vivo.\",\n      \"method\": \"Anti-CR1 and anti-CD46 antibody co-ligation; ELISA for cytokines; flow cytometry for CD25 and granzyme B; immunohistochemical staining of tonsil sections\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody co-ligation with multiple functional readouts plus in vivo tissue localization, single lab\",\n      \"pmids\": [\"25742728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human glomerular podocytes express CR1 as the sole C3 receptor type. Glomerular CR1 binds C3b-coated erythrocytes (not C3dg, C3d, or C3bi), shares functional and antigenic properties with peripheral blood CR1, and has decay-accelerating activity for the C3 convertase. Anti-CR1 F(ab')2 specifically inhibits binding, and immunoprecipitation of surface-labeled glomerular proteins yields CR1 of Mr 205,000.\",\n      \"method\": \"Rosette adherence assay with defined C3-fragment-coated erythrocytes; indirect immunofluorescence with anti-CR1, anti-CR2, anti-CR3 antibodies; complement convertase decay assay; 125I surface labeling and immunoprecipitation/SDS-PAGE\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (functional adherence, immunofluorescence, convertase decay, immunoprecipitation), replicated across three kidney donors\",\n      \"pmids\": [\"2418113\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CR1 (CD35) is a multi-modular complement regulatory glycoprotein with two principal ligand-binding sites (Site 1: CCPs 1–3; Site 2: CCPs 8–10 and 15–17) that bind C3b and C4b at distinct but partially overlapping surfaces, and an LHR-D site (CCPs 24–25) that binds the defense collagens C1q and MBL; it inhibits complement activation by decay-accelerating activity toward C3 and C5 convertases and by serving as a cofactor for factor I-mediated cleavage of C3b and C4b, is expressed on erythrocytes, phagocytes, B and T lymphocytes, follicular dendritic cells, and glomerular podocytes where it mediates immune complex transport/clearance, phagocytosis, and transmembrane signaling (NF-κB activation, Ca2+ mobilization, PLD activation, inhibitory signals in B and T cells), and undergoes tissue-specific phosphorylation by protein kinase C in phagocytic cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CR1 (CD35) is a modular complement regulatory glycoprotein that restrains complement activation through two complementary enzymatic activities — decay-acceleration of the C3 and C5 convertases and cofactor activity for factor I-mediated cleavage of C3b and C4b [#0, #4, #25]. Its ligand-binding architecture is organized into discrete sites: an N-terminal Site 1 (CCPs 1\\u20133) that mediates C4b binding and convertase decay, and a Site 2 (CCPs 8\\u201310 and 15\\u201317) that binds both C3b and C4b and supports their factor I-dependent cleavage [#4, #14]. Specificity within these modules is governed by defined residues — the principal C3b/C4b-binding module pair adopts an extended head-to-tail arrangement in which a basic surface patch on module 15/16 contacts the acidic \\u03b1'-chain segment of C3b, and two substitutions in CCP1/CCP2 are sufficient to convert a C4b-binding site into a C3b-binding one [#3, #13, #22]. CR1 also serves as a receptor for the defense collagens C1q and MBL, both binding a single CCP24\\u201325 module pair in LHR-D, thereby mediating erythrocyte adhesion and phagocytosis of opsonized particles [#1, #2, #24]. Beyond complement regulation, CR1 is an active signaling receptor: ligand engagement or antibody cross-linking on phagocytes triggers phospholipase D activation, Ca2+ mobilization, NF-\\u03baB translocation, and IL-1 production, whereas clustering on B and T lymphocytes delivers inhibitory signals that suppress proliferation and cytokine synthesis [#6, #8, #9, #10, #11]. CR1 is expressed on erythrocytes, phagocytes, lymphocytes, glomerular podocytes, and hypoxic endothelium, and is released both as proteolytically cleaved soluble CR1 from neutrophils and as membrane vesicles shed by podocytes into urine [#5, #15, #16, #17, #27]. It additionally functions as a CD4-independent entry receptor for complement-opsonized HIV and as an EBV receptor distinct from CD21 [#7, #20].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established that CR1 is the sole C3b receptor on glomerular podocytes with intrinsic convertase decay activity, extending its role beyond circulating cells to a tissue-resident regulator.\",\n      \"evidence\": \"Rosette adherence, immunofluorescence, convertase decay assay and surface immunoprecipitation on human glomeruli from three donors\",\n      \"pmids\": [\"2418113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which CCP modules mediate podocyte C3b binding\", \"Physiological consequence of podocyte CR1 loss not addressed\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Showed CR1 undergoes cell-type-restricted phosphorylation, linking the receptor to active signaling specifically in phagocytes.\",\n      \"evidence\": \"32PO4 metabolic labeling and immunoprecipitation after PMA/FMLP stimulation across phagocytic and non-phagocytic cells\",\n      \"pmids\": [\"3484510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase identity not directly demonstrated\", \"Phosphorylated cytoplasmic residues not mapped\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Resolved the molecular basis of ligand specificity by mapping distinct C4b and C3b recognition sites to the N-terminal SCRs of separate LHRs, defining CR1 as a multivalent regulator.\",\n      \"evidence\": \"Deletion mutagenesis of full-length CR1 in COS cells with rosetting and factor I cofactor assays\",\n      \"pmids\": [\"2972794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level contacts not defined\", \"Quantitative affinities for each site not measured\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Characterized CR1 as a more potent factor I cofactor for C4b than C3b, distinguishing it functionally from MCP.\",\n      \"evidence\": \"In vitro reconstituted cofactor cleavage of fluid-phase and liposome-bound C4b with pH and detergent titration\",\n      \"pmids\": [\"1386357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro reconstitution\", \"Cellular relevance of dual pH optima unresolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Refined the two-site model, defining Site 1 (CCP1-2) as C4b-specific cofactor and Site 2 (CCP8-9) as a dual C3b/C4b site, and showed modifications could augment both activities.\",\n      \"evidence\": \"Substitution mutagenesis in COS cells with ligand binding and cofactor cleavage readouts\",\n      \"pmids\": [\"8175757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish convertase decay contributions of each site\", \"Mechanism of activity enhancement unexplained\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Pinpointed the acidic C3b \\u03b1'-chain residues required for CR1 engagement, mapping the complement-side of the interface and distinguishing CR1 from factor H and MCP contact regions.\",\n      \"evidence\": \"Site-directed mutagenesis of C3 with factor I cofactor cleavage as surrogate binding readout\",\n      \"pmids\": [\"7963581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding affinities not measured\", \"Used cofactor activity as proxy for binding\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Determined that two point substitutions in CCP1/CCP2 are sufficient to graft C3b binding onto a C4b site, defining the residue determinants of ligand discrimination.\",\n      \"evidence\": \"Site-directed mutagenesis of truncated CR1 with rosetting and cofactor assays\",\n      \"pmids\": [\"8757632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the gained interaction not shown\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed murine CR1 collapses C3b and C4b recognition into a single SCR-1-dependent site, contrasting the multi-site human architecture.\",\n      \"evidence\": \"Murine CR1/human CR2 chimeric deletion constructs in K562 cells with rosetting\",\n      \"pmids\": [\"8144890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative affinity comparison to human CR1\", \"Cofactor activity of murine site not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identified soluble plasma CR1 as a proteolytic ectodomain product shed predominantly by neutrophils under inflammatory stimuli, defining a regulated release mechanism.\",\n      \"evidence\": \"Intracellular-domain-specific ELISA, SDS-PAGE size comparison and RT-PCR after PMN stimulation\",\n      \"pmids\": [\"7957565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease responsible not identified\", \"Cleavage site not mapped\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed podocyte CR1 is shed into urine as functional membrane vesicles, establishing a distinct vesicular release route from the proteolytic neutrophil pathway.\",\n      \"evidence\": \"Ultracentrifugation, lipid analysis, EM, renal transplant allotype discordance and C3b-binding assay\",\n      \"pmids\": [\"8113681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of vesicle formation not defined\", \"Functional fate of urinary CR1 unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified CR1 as a high-affinity C1q receptor binding via the collagen domain, expanding its repertoire beyond C3/C4 fragments.\",\n      \"evidence\": \"Radioligand binding to CR1-transfected K562 cells and SPR on immobilized rsCR1 with competition assays\",\n      \"pmids\": [\"9324355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CR1 module mediating C1q binding not localized in this study\", \"Cellular consequence of C1q engagement not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended the C3b acidic interface to residues 738\\u2013767 and showed CR1 contacts a wider segment than factor H, refining the convertase-regulator binding map.\",\n      \"evidence\": \"Charged-residue mutagenic scan of C3 with cofactor cleavage assays for CR1, factor H and MCP\",\n      \"pmids\": [\"9988761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of the CR1\\u2013C3b interface\", \"Proxy assay rather than direct binding\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated hypoxia induces functional CR1 on endothelial cells, identifying a regulated context-dependent expression site relevant to vascular complement control.\",\n      \"evidence\": \"ELISA, confocal colocalization, Western blot, in situ hybridization and cofactor activity in HUVECs\",\n      \"pmids\": [\"9950773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Predominantly intracellular localization fate unclear\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified CR1 as an MBL receptor sharing a binding site with C1q, linking it to lectin-pathway recognition and phagocytosis of opsonized bacteria.\",\n      \"evidence\": \"Radioligand binding to immobilized sCR1, competition with C1q, erythrocyte adhesion and PMN phagocytosis assays\",\n      \"pmids\": [\"11120776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise binding module not localized in this study\", \"Signaling downstream of MBL engagement not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided the structure of the principal C3b/C4b-binding module trio, revealing an extended flexible arrangement and the basic surface patches required for ligand contact.\",\n      \"evidence\": \"NMR structure of CCP15-17 with structure-guided mutagenesis and binding assays\",\n      \"pmids\": [\"11955431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of CR1 bound to C3b/C4b\", \"Full-length receptor architecture not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined CR1 as a negative regulator of B cell activation, showing ligand clustering inhibits BCR-driven proliferation and calcium signaling.\",\n      \"evidence\": \"Aggregated C3/C3(H2O) stimulation of tonsil B cells with proliferation, Ca2+ and phosphoprotein readouts\",\n      \"pmids\": [\"11884446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoplasmic signaling effectors not identified\", \"Single-lab antibody/ligand approach\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Dissected the spatial logic of convertase decay, showing Site 1 mediates dissociation while Site 2 binds C3b, and that tandem Site 1 copies act synergistically, implying a dimeric convertase target.\",\n      \"evidence\": \"Site mutant and tandem constructs with decay-accelerating activity assays for C3 and C5 convertases\",\n      \"pmids\": [\"16177096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed convertase dimer not structurally confirmed\", \"Single-lab functional assays\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established CR1 as an inhibitory T cell receptor acting downstream of immediate-early transcription to block cytokine protein synthesis and cell-cycle entry.\",\n      \"evidence\": \"Anti-CR1 stimulation of T cells with proliferation, RT-PCR and protein expression readouts\",\n      \"pmids\": [\"16360013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Translational/post-transcriptional mechanism not defined\", \"Physiological ligand in T cell context unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CR1 as an EBV entry receptor distinct from CD21, broadening its role in viral tropism.\",\n      \"evidence\": \"Retroviral transduction of CD21-negative cell lines with gp350/220 binding and latent infection readouts\",\n      \"pmids\": [\"23416052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CR1 module mediating gp350 binding not mapped\", \"In vivo contribution to EBV infection unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantified the intrinsic, non-internalizing protective action of epithelial CR1, showing strong reduction of C3b deposition by decay-acceleration plus progressive cofactor cleavage.\",\n      \"evidence\": \"CHO podocyte model with classical/alternative pathway deposition, cleavage kinetics and internalization assays\",\n      \"pmids\": [\"26260209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Model cell system rather than primary podocytes\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CR1 co-ligation with CD46 on CD4+ T cells drives a regulatory phenotype, implicating CR1 in adaptive immune tolerance.\",\n      \"evidence\": \"Anti-CR1/anti-CD46 co-ligation with cytokine ELISA, flow cytometry and tonsil immunohistochemistry\",\n      \"pmids\": [\"25742728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic crosstalk between CR1 and CD46 signaling not defined\", \"Antibody co-ligation rather than natural ligand\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized both C1q and MBL binding to a single CCP24\\u201325 module pair in LHR-D, unifying the defense-collagen recognition site and distinguishing C1q (collagen plus head sites) from MBL (collagen only).\",\n      \"evidence\": \"CR1 deletion variants (isolated CCP24-25; CCP22-30 lacking CCP24-25) with binding and competition assays\",\n      \"pmids\": [\"29563915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of CR1 with C1q or MBL\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CR1 ligand engagement is transduced into the distinct activating (phagocyte) versus inhibitory (lymphocyte) intracellular signals, including the kinases and cytoplasmic effectors involved, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined cytoplasmic signaling adaptors identified\", \"PKC isoform and phosphosites not mapped\", \"No structure of CR1 in complex with its complement or collagen ligands\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 14, 25]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7, 20]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 2, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 16, 27]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [15, 16, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C3b\", \"C4b\", \"C1q\", \"MBL\", \"CFI\", \"CD46\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}